A Phase 0 Trial of Ceritinib in Patients with Brain Metastases and Recurrent Glioblastoma
| Autor: | Roberto Fiorelli, Chelsea Pennington-Krygier, Jing Li, Wonsuk Yoo, Xun Bao, Seongho Kim, Alanna Derogatis, Nader Sanai, Shwetal Mehta |
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| Rok vydání: | 2022 |
| Předmět: |
Cancer Research
Lung Neoplasms Brain tumor Cerebrospinal fluid Pharmacokinetics Tandem Mass Spectrometry Humans Medicine Anaplastic Lymphoma Kinase Sulfones Protein Kinase Inhibitors Ceritinib Brain Neoplasms business.industry medicine.disease Blood proteins Pyrimidines Oncology Pharmacodynamics Cancer research Immunohistochemistry Neoplasm Recurrence Local Glioblastoma business Chromatography Liquid Brain metastasis medicine.drug |
| Zdroj: | Clinical Cancer Research. 28:289-297 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Ceritinib is an orally bioavailable, small-molecule inhibitor of anaplastic lympoma kinase (ALK), insulin-like growth factor 1 receptor (IGFR1), and focal adhesion kinase (FAK), which are highly expressed in glioblastoma and many brain metastases. Preclinical and clinical studies indicate that ceritinib has antitumor activity in central nervous system (CNS) malignancies. This phase 0 trial measured the tumor pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in patients with brain metastasis or recurrent glioblastoma. Patients and Methods: Preoperative patients with brain tumors demonstrating high expression of pSTAT5b/pFAK/pIGFR1 were administered ceritinib for 10 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at predefined timepoints following the final dose. Total and unbound drug concentrations were determined using LC-MS/MS. In treated tumor and matched archival tissues, tumor PD was quantified through IHC analysis of pALK, pSTAT5b, pFAK, pIGFR1, and pIRS1. Results: Ten patients (3 brain metastasis, 7 glioblastoma) were enrolled and no dose-limiting toxicities were observed. Ceritinib was highly bound to human plasma protein [median fraction unbound (Fu), 1.4%] and to brain tumor tissue (median Fu, 0.051% and 0.045% in gadolinium-enhancing and -nonenhancing regions respectively). Median unbound concentrations in enhancing and nonenhancing tumor were 0.048 and 0.006 μmol/L, respectively. Median unbound tumor-to-plasma ratios were 2.86 and 0.33 in enhancing and nonenhancing tumor, respectively. No changes in PD biomarkers were observed in the treated tumor samples as compared to matched archival tumor tissue. Conclusions: Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations achieved in brain metastases and patients with recurrent glioblastoma were insufficient for target modulation. |
| Databáze: | OpenAIRE |
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